Animal investigations have clearly demonstrated the relevance of spinal opioid receptors to pain transmission and the relative safety of opiates administered by this route. Such insights have led to the subsequent extensive use of spinal opiates in post-operative and terminal cancer patients. In addition, the ability to easily and reliably catheterize the intrathecal space has permitted an intensive examination of the pharmacological characteristics of spinal opioid receptors linked to spinal substrates processing pain information. The present proposal represents a continuation of these primary studies initiated in this laboratory to study these spinal systems in rat and primate. In the present work, we will continue to characterize the opiate receptors: 1) with structure-activity studies carried out with a variety of intrathecally administered opioid ligands in the rat on the cutaneous thermal/visceral chemical measures and in the primate on the shock titration; 2) by establishing the characteristics (pA2) of the opioid antagonist in the presence of mu, delta and kappa agonists on these nociceptive endpoints; 3) by examination of the effects of non-equilibrium antagonists, Beta-chlornaltrexamine, Beta-funalnaltrexamine and naloxonazine. In addition, tolerance to spinally administered opiates is one of the problems encountered with the chronic administration of opiates for terminal cancer pain. Tolerance and cross tolerance also represents a methodology to define receptors. In these studies, a particular emphasis will be placed on the characteristics of tolerance onset and reversal in rats and primates. The effects of opiate receptor antagonism on this time course of tolerance reversal will be examined. These studies are, as were our previous observations on the characteristics of spinally administered agents in the animal models, clearly relevant to the long term amelioration of pain in man.